In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV). Numerous compounds have since been synthesized to combat the virus, designed to inhibit progression beyond various stages of the virus's lifecycle. A focal point in AIDS research efforts has been the development of inhibitors of human immunodeficiency virus (HIV-1) reverse transcriptase (RT), an enzyme responsible for the reverse transcription of the retroviral RNA to proviral DNA (Greene, W. C., New England Journal of Medicine, 1991, 324, 308-317; Mitsuya, H. et al., Science, 1990, 249, 1533-1544; De Clercq, E., J. Acquired Immune Defic. Syndr. Res. Human. Retrovirus, 1992, 8, 119-134). Promising inhibitors include nonnucleoside reverse transcriptase inhibitors (NNRTIs), which bind to a specific allosteric site of HIV-1 RT near the polymerase site and interfere with reverse transcription by altering either the conformation or mobility of RT, thereby leading to noncompetitive inhibition of the enzyme (Kohlstaedt, L. A. et al., Science, 1992, 256, 1783-1790).
Several classes of compounds have been identified as NNRTIs of HIV-1. Examples include the following:    (a) 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPT; Tanaka, H. et al., J. Med. Chem., 1991, 34, 349-357; Pontikis, R. et al., J. Med. Chem., 1997, 40, 1845-1854; Danel, K., et al., J. Med. Chem., 1996, 39, 2427-2431; Baba, M., et al., Antiviral Res, 1992, 17, 245-264);    (b) bis(heteroaryl)piperazines (BHAP; Romero, D. L. et al., J. Med. Chem., 1993, 36, 1505-1508);    (c) dihydroalkoxybenzyloxopyrimidine (DABO; Danel, K. et al., Acta Chemica Scandinavica, 1997, 51, 426-430; Mai, A. et al., J. Med. Chem., 1997, 40, 1447-1454);    (d) 2′-5′-bis-O-(tertbutyldimethylsilyl)-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) pyrimidines (TSAO; Balzarini, J. et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 4392-4396);    (e) phenethylthiazolylthiourea (PETT) derivatives (Bell, F. W. et al., J. Med. Chem., 1995, 38, 4929-4936; Cantrell, A. S. et al., J. Med. Chem., 1996, 39, 4261-4274);    (f) tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and -thione (TIBO) derivatives (Pauwels, R. et al. Nature, 1990, 343, 470-474);    (g) alpha-anilinophenylacetamide (alpha-APA) derivatives (Pauwels, R. et al. Proceedings of the National Academy of Sciences USA, 1993, 90, 1711-1715); and    (h) indole derivatives (Williams et al., U.S. Pat. No. 5,527,819 (Jun. 18, 1996); and its counterpart PCT application PCT/US94/01694, published as WO 94/19321 on Sep. 1, 1994).
The indole derivatives identified by Williams et al., assigned to Merck & Co., in U.S. Pat. No. 5,527,819 received particular interest because of their ability to inhibit potently HIV reverse transcriptase. A number of these compounds displayed EC90's against HIV reverse transcriptase at concentrations as low as 2 micromolar. However, while this work was not pursued, it resulted in a novel process for synthesizing optionally substituted indoles by a palladium-catalyzed annulation between a ketone and an iodoaniline (Chen et al., J. Org. Chem., 1997, 62(9): 2676-77).
The compounds disclosed in the '819 patent comprise a large class represented generally by the following broad structural formula:
in which the variables X, Y, Z, R and R6 were broadly defined to encompass a plethora of compounds. The patent presented examples for nearly one hundred of the compounds encompassed by the structure, and included several examples in which Z was —C(O)NH2, Y was SO2 and R was phenyl or substituted phenyl.
U.S. Pat. No. 5,124,327, issued Jun. 23, 1992 to Greenlee et al. and assigned to Merck disclosed a class of compounds of the general formula above, in which X is H, R6 is H, Y is S, and R is phenyl. The patent disclosed that the compounds act as reverse transcriptase inhibitors.
WO 02/083126 to Idenix Pharmaceuticals, Ltd., disclosed a class of phenylindoles substituted with at least two moieties other than hydrogen on either the phenyl ring or the benzyl ring of the indole function, or on both rings. The substituents are preferably contained at the 3″ and 5″ positions if located on phenyl ring, and at the 4′ and 5′; 5′ and 6′ or the 5′ and 7′ positions if located on the benzyl ring of the indole function.
Indoles have been used for the treatment of a variety of diseases other than HIV. For example, Farina et al., in U.S. Pat. No. 5,981,525 (Nov. 9, 1999), disclose a complex array of indoles that are useful for the treatment of osteoporosis, because they reduce bone resorption by inhibiting osteoclast H+-ATPase.
U.S. Pat. No. 6,025,390, granted Feb. 15, 2000 to Farina et al., discloses another complex array of indole derivatives, referred to as heteroaromatic pentadienoic acid derivatives, and again suggest their use for the treatment of osteoporosis.
U.S. Pat. No. 5,489,685, granted Feb. 6, 1996, Houpis et al. discloses a similar set of compounds in the furo(2,3-b) pyridine carboxylic acid ester class, and specifically suggest their use for the treatment of HIV.
U.S. Pat. No. 5,945,440 to Kleinschroth et al. discloses a class of indolocarbazole amides, and proposes their use for a variety of diseases including cancer, viral diseases (including HIV), heart and blood vessel diseases, bronchopulmonary diseases, degenerative diseases of the central nervous system, inflammatory disorders, and other diseases.
Gunasekera et al., in U.S. Pat. No. 4,866,084 (Sep. 12, 1989), disclose a class of bisindole alkaloid compounds, and state that the compounds are useful as antiviral and antitumor agents. The patent also describes the compounds' activity against HSV (herpes simplex virus).
Matsunaga et al., in U.S. Pat. No. 5,852,011 (Dec. 22, 1998), disclose a class of indole derivatives substituted by a heteroaryl function and an amide function.
The compounds are said to possess antitumor, antiviral, and antimicrobial properties.
Dykstra et al., in U.S. Pat. No. 5,935,982 disclose a class of bis-indoles and specifically propose their use for treating retroviral infections, and especially infection by HIV.
Domagala et al., in U.S. Pat. No. 5,929,114 (Jul. 27, 1999) disclose a class of arylthio and bithiobisarylamide compounds that reportedly have antibacterial and antiviral activity. The invention is said to encompass indole derivatives as well.
Pevear et al., in U.S. Pat. No. 5,830,894 (Nov. 3, 1998) disclose a class of triazinoindole derivatives that reportedly have anti-pestivirus activity, most notably BVDV activity.
It is known that over a period of time, antiviral agents that are active against HIV induce mutations in the virus that reduce the efficacy of the drug. This was apparently the problem exhibited by the Merck indoles in U.S. Pat. No. 5,527,819 (Williams et al., Journal of Medicinal Chemistry, 1993, 36(9), 1291-94). Drug resistance most typically occurs by mutation of a gene that encodes an enzyme used in viral replication, and most typically in the case of HIV, reverse transcriptase, protease, or DNA integrase. It has been demonstrated that the efficacy of a drug against HIV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principal drug. Alternatively, the pharmacokinetics, biodistribution, or other parameters of a drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy since combination therapy induces multiple simultaneous pressures on the virus. However, one cannot predict which mutations will be induced in the HIV-1 genome by a given drug, whether the mutations are permanent or transient, or how an infected cell with a mutated HIV-1 sequence will respond to therapy with other agents in combination or alternation. These factors are exacerbated by the fact that there is a paucity of data on the kinetics of drug resistance in long-term cell cultures treated with modern antiretroviral agents.
Therefore, there is a need to improve the duration of antiviral efficacy produced by antiretroviral drugs, and to provide antiviral drugs that are effective against strains of the virus that have developed cross resistance through mutational adaptation. Further, although many of the non-nucleotide reverse transcriptase inhibitors (NNRTI) in the prior art exhibit favorable pharmacokinetic and biodistribution profiles, there remains a need to improve upon these parameters.
It is an object of the present invention to provide new compounds for the treatment of patients infected with HIV. There is a special need to provide new compositions and methods for the treatment of patients infected with HIV that exhibit significant activity against drug-resistant forms of the virus.